Plain language summary
Phytanic acid (PA) is a branched-chain fatty acid, found in many animal products, that, unlike most fatty acids, cannot be metabolised by beta-oxidation. Instead, it undergoes alpha-oxidation in the peroxisome. Adult Refsum Disease is a genetic neurological disease, in which alpha-oxidation is impaired, resulting in the accumulation of PA in nerves and fat tissues. Other pathways for the metabolism of PA are not fully understood, such as omega-oxidation, which results in the production of 3-methyl-organic acids (3-MAA). This study assessed the contribution of the omega-oxidation pathway to the metabolism of PA by measuring 3-MAA excretion in patients with ARD. Eleven patients with ARD were put on a low-PA diet for 12 weeks. Blood, urine and tissue samples were taken at the start and end of the 12-week period to assess levels of PA and its metabolites. The low-PA diet led to an average 21% fall in blood PA levels over 12 weeks. The capacity of the omega-oxidation pathway was 6.9mg PA/day. The authors concluded that the omega-oxidation pathway can metabolise PA ingested by patients with ARD. Therefore, omega-oxidation is a potential target for therapeutic intervention to reduce PA levels in ARD patients.
Abstract
Adult Refsum disease (ARD) is associated with defective alpha-oxidation of phytanic acid (PA). omega-Oxidation of PA to 3-methyl-adipic acid (3-MAA) occurs although its clinical significance is unclear. In a 40 day study of a new ARD patient, where the plasma half-life of PA was 22.4 days, omega-oxidation accounted for 30% initially and later all PA excretion. Plasma and adipose tissue PA and 3-MAA excretion were measured in a cross-sectional study of 11 patients. The capacity of the omega-oxidation pathway was 6.9 (2.8-19.4) mg [20.4 (8.3-57.4) micromol] PA/day. 3-MAA excretion correlated with plasma PA levels (r = 0.61; P = 0.03) but not adipose tissue PA content. omega-Oxidation during a 56 h fast was studied in five patients. 3-MAA excretion increased by 208 +/- 58% in parallel with the 158 (125-603)% rise in plasma PA. Plasma PA doubled every 29 h, while 3-MAA excretion followed second-order kinetics. Acute sequelae of ARD were noted in three patients (60%) after fasting. The omega-oxidation pathway can metabolise PA ingested by patients with ARD, but this activity is dependent on plasma PA concentration. omega-Oxidation forms a functional reserve capacity that enables patients with ARD undergoing acute stress to cope with limited increases in plasma PA levels.
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